Case 52216A
-1Claims
1. A compound of the formula
R4
R5
R6
R7
S
N
R3
R8
R2
R9
N
R1
OH
(I),
R10
H
in which
R1 is hydrogen; halogen; or (C1-8)alkyl;
R2 is hydrogen; halogen; (C1-8)alkyl; halogen-(C1-8)alkyl; (C1-8)alkoxy; or halogen(C1-8)alkoxy;
either
R3 is hydrogen; and
R4 is hydrogen; (C1-8)alkoxy-(C1-8)alkyl; (C1-8)alkylcarbonyloxy-(C1-8)alkyl; formyl;
(C1-8)alkylcarbonyl; or (C1-8)alkoxycarbonyl;
or
R3 is halogen-(C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; formyl; (C1-8)alkylcarbonyl; (C3-8)cycloalkylcarbonyl; (C3-8)cycloalkyl-(C1-8)alkylcarbonyl; halogen-(C1-8)alkylcarbonyl; (C1-8)alkoxycarbonyl; halogen-(C1-8)alkoxycarbonyl; or an aryl-(C1-8)alkyl group,
which aryl-(C1-8)alkyl group is optionally ring-substituted by 1 to 4 substituents independently
selected from the group, consisting of halogen, (C1-8)alkyl, halogen-(C1-8)alkyl, (C1-8)alkoxy(C1-8)alkyl, halogen-(C1-8)alkoxy-(C1-8)alkyl, (C3-8)cycloalkyl, (C1-8)alkoxy and halogen-(C1-8)alkoxy; and
R4 is hydrogen; (C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; (C1-8)alkylcarbonyloxy-(C1-8)alkyl;
formyl; (C1-8)alkylcarbonyl; or (C1-8)alkoxycarbonyl;
R5 is hydrogen; halogen; (C1-8)alkyl; halogen-(C1-8)alkyl; halogen-(C1-8)alkyl
substituted by hydroxy; halogen-(C1-8)alkyl substituted by (C1-8)alkoxy; amino-(C1-8)alkyl; N(C1-8)alkylamino-(C1-8)alkyl; N,N-di-[(C1-8)alkyl]amino-(C1-8)alkyl with two identical or different
(C1-8)alkyl moieties in the N,N-di-[(C1-8)alkyl]amino moiety; (C2-8)alkenyl; (C3-8)cycloalkyl-(C28)alkenyl;
halogen-(C2-8)alkenyl; (C1-8)alkoxy; halogen-(C1-8)alkoxy; halogen-(C1-8)alkoxy
substituted by hydroxy; halogen-(C1-8)alkoxy substituted by (C1-8)alkoxy; halogen-(C1-8)alkoxy
substituted by amino; halogen-(C1-8)alkoxy substituted by N-(C1-8)alkylamino; halogen-(C18)alkoxy
substituted by N,N-di-[(C1-8)alkyl]amino with two identical or different (C1-8)alkyl
moieties, which two (C1-8)alkyl moieties, taken together, can complete, together with the
Case 52216A
-2nitrogen atom, to which they are attached, a ring with 3 to 7 ring members; (C1-8)alkoxy-(C18)alkyl;
halogen-(C1-8)alkoxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkoxy; halogen-(C1-8)alkoxy-(C1-
8)alkoxy;
(C1-8)alkoxy-(C1-8)alkoxy-(C1-8)alkyl; halogen-(C1-8)alkoxy-(C1-8)alkoxy-(C1-8)alkyl;
formyl; (C1-8)alkylcarbonyl; (C3-8)cycloalkylcarbonyl; (C3-8)cycloalkyl-(C1-8)alkylcarbonyl;
halogen-(C1-8)alkylcarbonyl; aminocarbonyl; N-(C1-8)alkylaminocarbonyl optionally substituted
by halogen; N,N-di-[(C1-8)alkyl]aminocarbonyl with two identical or different (C1-8)alkyl
moieties, which two identical or different (C1-8)alkyl moieties can be substituted, identically or
differently, by halogen; N-(C3-8)cycloalkylaminocarbonyl; N-[(C3-8)cycloalkyl-(C18)alkyl]aminocarbonyl;
8)cycloalkyl,
(C1-8)alkoxycarbonyl; halogen-(C1-8)alkoxycarbonyl; or a (C3-
(C3-8)cycloalkyl-(C1-8)alkyl, (C3-8)cycloalkyl-(C1-8)alkoxy, (C3-8)cycloalkoxy, aryl,
aryloxy, heteroaryl, heteroaryloxy, non-aromatic heterocyclyl or non-aromatic heterocyclyloxy
group, which (C3-8)cycloalkyl, (C3-8)cycloalkyl-(C1-8)alkyl, (C3-8)cycloalkyl-(C1-8)alkoxy, (C38)cycloalkoxy,
aryl, aryloxy, heteroaryl, heteroaryloxy, non-aromatic heterocyclyl or non-
aromatic heterocyclyloxy group is optionally ring-substituted by 1 to 4 substituents
independently selected from the group, consisting of halogen, (C1-8)alkyl, halogen-(C1-8)alkyl,
(C1-8)alkoxy-(C1-8)alkyl, halogen-(C1-8)alkoxy-(C1-8)alkyl, (C3-8)cycloalkyl, (C1-8)alkoxy and
halogen-(C1-8)alkoxy;
either
R6 is absent; and
R7 is absent;
or
R6 is oxo; and
R7 is absent;
or
R6 is oxo; and
R7 is oxo; imino; (C1-8)alkylimino; benzylimino; formylimino; or (C1-8)alkylcarbonylimino;
either
R8 is hydrogen; (C1-8)alkyl; halogen-(C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; or a (C3-8)cycloalkyl group, which (C3-8)cycloalkyl group is optionally substituted by 1 to
4 substituents independently selected from the group, consisting of halogen and (C1-8)alkyl;
and
R9 is hydrogen; (C1-8)alkyl; halogen-(C1-8)alkyl; hydroxy-(C1-8)alkyl; (C1-8)alkoxy-(C1-8)alkyl; or a (C3-8)cycloalkyl group, which (C3-8)cycloalkyl group is optionally substituted by 1 to
4 substituents independently selected from the group, consisting of halogen and (C1-8)alkyl;
Case 52216A
-3or
R8 and R9, taken together, complete, together with the carbon atom, to which they
are attached, a (C3-8)cycloalkylidene moiety, in which (C3-8)cycloalkylidene moiety 1 of its
-CH2- ring members can be replaced with -O-; and
R10 is an aryl or heteroaryl group, which aryl or heteroaryl group is optionally mono-,
di-, tri- or tetra-substituted by substituents independently selected from the group, consisting
of (i) the univalent substituents halogen, hydroxy, (C1-8)alkyl, halogen-(C1-8)alkyl, hydroxy-(C18)alkyl,
hydroxy-(C1-8)alkyl substituted by halogen, (C1-8)alkoxy-(C1-8)alkyl, halogen-(C1-
8)alkoxy-(C1-8)alkyl,
cyano-(C1-8)alkyl, (C1-8)alkoxy, halogen-(C1-8)alkoxy, a heteroaryl group,
which heteroaryl group is optionally substituted by 1 to 4 substituents independently selected
from the group, consisting of halogen, (C1-8)alkyl and halogen-(C1-8)alkyl, and a (C38)cycloalkyl
group, in which (C3-8)cycloalkyl group 1 of its -CH2- ring members can be
replaced with -O-, and which (C3-8)cycloalkyl group, in which 1 of its -CH2- ring members is
optionally replaced with -O-, is optionally substituted by 1 to 4 substituents independently
selected from the group, consisting of halogen, (C1-8)alkyl and halogen-(C1-8)alkyl, and (ii) the
bivalent substituents (C3-16)alkylene, oxa-(C2-16)alkylene and (C1-8)alkylenoxa-(C1-8)alkylene,
any such optional bivalent substituent being attached to two adjacent ring carbon atoms of
the aryl or heteroaryl group,
in free form or in salt form.
2. A process for the preparation of a compound as defined in claim 1 of the formula I, in free
form or in salt form, comprising the steps of
a) for the preparation of a compound of the formula I, in free form or in salt form, in which R3
is hydrogen and R4 is hydrogen, treatment of a compound of the formula
R5
Ra
R6
R7
S
R8
R2
N
R1
OH
R9
(II),
R10
H
in which Ra is azido or nitro and all of the other variables are as defined for the formula I, in
free form or in salt form, with a reducing agent, in order to convert Ra into amino, or
b) for the preparation of a compound of the formula I, in free form or in salt form, in which R8
is hydrogen, treatment of a compound of the formula
Case 52216A
-4R4
R5
R6
R7
S
N
R3
(III),
R9
R2
N
R1
OH
R10
in which all of the variables are as defined for the formula I, in free form or in salt form, with a
reducing agent, in order to convert the moiety -N=C(R9)R10 into the moiety
-N(H)-C(H)(R9)R10,
in each case optionally followed by reduction, oxidation or other functionalisation of the resulting compound and/or by cleavage of any protecting group(s) optionally present,
and of recovering the so obtainable compound of the formula I in free form or in salt form.
3. A compound as defined in claim 1, in free form or in pharmaceutically acceptable salt
form, for use as a medicament.
4. A compound as defined in claim 1, in free form or in pharmaceutically acceptable salt
form, for use in the treatment of neurological or vascular disorders related to beta-amyloid
generation and/or aggregation.
5. A pharmaceutical composition comprising a compound as defined in claim 1, in free form
or in pharmaceutically acceptable salt form, as active ingredient and a pharmaceutical carrier
or diluent.
6. The use of a compound as defined in claim 1, in free form or in pharmaceutically acceptable salt form, as a medicament for the treatment of neurological or vascular disorders related to beta-amyloid generation and/or aggregation.
7. The use of a compound as defined in claim 1, in free form or in pharmaceutically acceptable salt form, for the manufacture of a medicament for the treatment of neurological or
vascular disorders related to beta-amyloid generation and/or aggregation.
8. A method for the treatment of neurological or vascular disorders related to beta-amyloid
generation and/or aggregation in a subject in need of such treatment, which comprises
Case 52216A
-5administering to such subject a therapeutically effective amount of a compound as defined in
claim 1, in free form or in pharmaceutically acceptable salt form.
9. A combination comprising a therapeutically effective amount of a compound as defined in
claim 1, in free form or in pharmaceutically acceptable salt form, and a second drug substance, for simultaneous or sequential administration.